Process for preparing 1-bromoalkylbenzene derivatives and intermediates thereof

ABSTRACT

A 1-bromoalkylbenzene derivative is prepared by reacting a phenylalkene derivative with hydrogen bromide in the presence of a non-polar solvent. The phenylalkene derivative is prepared by reacting an alkenyl halide with metal magnesium to form a Grignard reagent, and then reacting the Grignard reagent with a benzyl halide derivative. An allyl Grignard reagent is prepared by reacting continuously an allyl halide derivative with metal magnesium in an organic solvent, in which the allyl halide derivative and metal magnesium are continuously added to the reaction system and the allyl Grignard reagent formed is continuously removed from the reaction system. The processes provide the intended compounds in high yields, high selectivities and high purities.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of Ser. No. 08/286,411, filed on Aug.5, 1994 now U.S. Pat. No. 5,637,736, the entire contents of which arehereby incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a process for preparing a1-bromoallkylbenzene derivative. The invention also relates to a processfor preparing an allyl Grignard reagent which can be an intermediate ofthe 1-bromoallkylbenzene derivative.

2. Description of the Related Art

1-Bromoalkylbenzene derivatives are useful substances as intermediatesfor medicines, agrochemicals, etc. For example, they can be importantintermediates of the compound of the formula: ##STR1## which is usefulas a medicine.

A 1-bromoalkylbenzene derivative of the general formula: ##STR2##wherein R represents a hydrogen atom, a lower alkyl group or a loweralkoxy group, and n is an integer of 1 to 8, may be prepared by reactinga phenylalkene derivative of the general formula: ##STR3## wherein R andn are the same as defined above, with hydrogen bromide. However, whenthe reaction of the phenylalkene derivatives of the general formula (X)with hydrogen bromide is carried out by conventional methods, forexamples, using (1) an aqueous hydrobromic acid solution, or (2) ahydrobromic acid solution in acetic acid or propionic acid, there areproblems that the reaction does not proceeds, or the selectivity of the1-bromoalkylbenzene of the general formula (IX) is low and the isomer ofthe general formula: ##STR4## wherein R and n are the same as definedabove, is by-produced.

On the other hand, it is known to prepare the phenylalkene of thegeneral formula (X) in which R is H and n is 2 in the following twoways: One process comprise the step of reacting phenetyl magnesiumbromide with vinyl chloride in the presence of nickel acetylacetonate toobtain 4-phenyl-1-butene. The other process comprises the steps ofreacting toluene with 1,3-butadiene in the presence of sodium to form5-phenyl-2-pentene and then reacting it with ethylene in the presence oftetrabutyl tin and rhenium oxide to obtain 4-phenyl-1-butene.

However, both of the above processes are not satisfactory since they usesodium which is difficult to handle industrially, or use expensivecatalysts.

It is known to prepare an allyl Grignard reagent in the following twoways: One process comprises the step of adding one mole of allylchloride to 2.4 moles of magnesium in tetrahydrofuran which is cooled to-15° C. over a period of 12 hours to obtain allyl magnesium chloride.The other process comprises the step of adding dropwise one mole ofallyl bromide to 2.4 mole of magnesium in tetrahydrofuran which iscooled to 0° C. over a period of 17 hours to obtain allyl magnesiumbromide.

However, the processes use a large amount of the solvent, require thelong periods of reaction time at the low temperatures and, in addition,are difficult to obtain the products in high yields since Wurtz-typereactions proceed rapidly (see Org. Syn., Coll. Vol. IV, p 749).

SUMMARY OF THE INVENTION

It is an object of the present invention to provide an industriallyadvantageous novel process for preparing a 1-bromoalkylbenzenederivative.

It is another object of the present invention to provide a process forpreparing an allyl Grignard reagent which can be an intermediate of the1-bromoalkylbenzene derivative.

The present invention provides a process for preparing a1-bromoalkylbenzene derivative of the general formula: ##STR5## whereinR¹, R² and R³ independently represent a hydrogen atom, a halogen atom, alower alkyl group containing 1 to 5 carbon atoms or a lower alkoxy groupcontaining 1 to 5 carbon atoms, or R¹ and R² together form amethylenedioxy group or an ethylenedioxy group when R³ is a hydrogenatom, and n is an integer of 1 to 8, comprising the step of reacting aphenylalkene derivative of the general formula: ##STR6## wherein R¹, R²,R³ and n are the same as defined above, with hydrogen bromide in thepresence of a non-polar solvent to form the 1-bromoalkylbenzenederivative of the general formula (I).

The phenylalkene derivative of the general formula (II) can be preparedby a process comprising the steps of reacting an alkenyl halide of thegeneral formula:

    CH.sub.2 ═CH--(CH.sub.2).sub.n-1 --X                   (III)

wherein X represents a chlorine atom or a bromine atom, and n is thesame as defined above, with metal magnesium to form a Grignard reagentof the general formula:

    CH.sub.2 ═CH--(CH.sub.2).sub.n-1 --MgX                 (IV)

wherein X and n are the same as defined above; and then reacting theGrignard reagent of the general formula (IV) with a benzyl halidederivative of the general formula: ##STR7## wherein R¹, R², R³ and X arethe same as defined above, to form the phenylalkene derivative of thegeneral formula (II).

The present invention also provides a process for preparing an allylGrignard reagent of the general formula: ##STR8## wherein R⁴, R⁵ and R⁶independently represent a hydrogen atom or an alkyl group containing 1to 4 carbon atoms and X is the same as defined above, comprising thestep of reacting an allyl halide derivative of the general formula:##STR9## wherein R⁴, R⁵, R⁶ and X are the same as defined above, withmetal magnesium in an organic solvent to form the allyl Grignard reagentof the general formula (VI), wherein the allyl halide derivative of thegeneral formula (VII) and metal magnesium are continuously added to thereaction system and the allyl Grignard reagent of the general formula(VI) formed is continuously removed from the reaction system.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, a 1-bromoalkylbenzene derivative ofthe general formula (I) is prepared from hydrogen bromide and aphenylalkene derivative of the general formula (II), which can bederived from a benzyl halide derivative of the general formula (V) and aGrignard reagent of the general formula (IV).

At first, the process for preparing the phenylalkene derivative of thegeneral formula (II) according to the present invention will beillustrated.

For this purpose, the alkenyl halide of the general formula (III) isreacted with metal magnesium to form the Grignard reagent of the generalformula (IV).

Specific examples of the alkenyl halide used are vinyl chloride, allylchloride, 4-chloro-1-butene, 5-chloro-1-pentene, 6-chloro-1-hexene,7-chloro-1-heptene, 8-chloro-1octene,9-chloro-1nonene, vinyl bromide,allyl bromide, 4-bromo-1-butene, 5-bromo-1-pentene, 6-bromo-1-hexene,7-bromo-1-heptene, 8-bromo-1-octene, 9-bromo-1-nonene, etc.

The alkenyl halide is usually used in an amount of 0.5 to 1.5 moles,preferably 1 to 1.3 moles per mole of metal magnesium. When the amountof the alkenyl halide exceeds 1.5 moles, a Wurtz-type reaction tends tooccur, which lowers the yield of the Grignard reagent.

The reaction may be carried out in the presence of a solvent. Preferredexamples of the solvent are tetrahydrofuran, or a mixed solvent thereofwith tert.-butyl methyl ether or an aromatic hydrocarbon such asbenzene, toluene, xylene, etc. From the view point of solvent recovery,the mixed solvent of tetrahydrofuran with tert.-butyl methyl ether or anaromatic hydrocarbon is more preferred than tetrahydrofuran alone. Whenthe mixed solvent is used, the mixing ratio is determined depending onthe kind of the solvent used. For example, in the case of thetetrahydrofuran--tert.-butyl methyl ether mixed solvent, a volume ratioof tert.-butyl methyl ether to tetrahydrofurane is from 0.1 to 3,preferably from 0.5 to 1.5. In the case of the tetrahydrofuran--toluenemixed solvent, a volume ratio of toluene to tetrahydrofuran is from 0.1to 9, preferably from 0.4 to 5.5. A higher mixing ratio is preferred inorder to reduce the amount of tetrahydrofuran used. However, when themixing ratio exceeds the above limit, the desired Grignard reagentcannot be prepared efficiently. From the view point of stirring of areaction mass in the next step, a too low mixing ratio is not preferred.

The solvent is used in an amount of 5 to 30 times, preferably 8 to 20times the alkenyl halide by weight. When the solvent is less than theabove amount, the Wurtz-type reaction is apt to occur, decreasing theyield of the Grignard reagent. On the other hand, the excessive use ofthe solvent is uneconomical although the yield is not affected.

The reaction may be carried out at a temperature of -50 to 50° C.,preferably -10 to 20° C. When the reaction temperature exceeds 50° C.,the Wurtz-type reaction tends to occur and the yield of the Grignardreagent is decreased.

The reaction may be carried out by adding dropwise the alkenyl halide toa mixture of metal magnesium and the solvent with stirring.

Then the phenylalkene derivative of the general formula (II) is preparedby reacting the Grignard reagent of the general formula (IV) obtainedabove with a benzyl halide derivative of the general formula (V).

R¹, R² and R³ in the benzyl halide derivative of the general formula (V)include a hydrogen atom, a fluorine atom, a chlorine atom, a bromineatom, an iodine atom, a methyl group, an ethyl group, a propyl group, abutyl group, a methoxy group, an ethoxy group, a propoxy group, a butoxygroup, etc.

Specific examples of the benzyl halide derivative are benzyl chloride,fluorobenzyl chloride, chlorobenzyl chloride, bromobenzyl chloride,iodobenzyl chloride, methylbenzyl chloride, ethylbenzyl chloride,propylbenzyl chloride, butylbenzyl chloride, methoxybenzyl chloride,ethoxybenzyl chloride, propoxybenzyl chloride, butoxybenzyl chloride,benzyl bromide, fluorobenzyl bromide, chlorobenzyl bromide, bromobenzylbromide, iodobenzyl bromide, methylbenzyl bromide, ethylbenzyl bromide,propylbenzyl bromide, butylbenzyl bromide, methoxybenzyl bromide,ethoxybenzyl bromide, propoxybenzyl bromide, and butoxybenzyl bromide,wherein the subsituents in the benzyl group may be positioned at any ofR¹, R² and R³ ; and 3,4-methylenedioxybenzyl chloride,3,4-methylenedioxybenzyl bromide, 3,4-ethylenedioxybenzyl chloride,3,4-ethylenedioxybenzyl bromide, etc.

The benzyl halide derivative is used in amount of 0.2 to 1.2 moles,preferably 0.4 to 1 mole per mole of the Grignard reagent.

The reaction is carried out optionally in the presence of a catalyst.Although the reaction proceeds without the catalyst, the use of thecatalyst accelerates the reaction to give a higher yield of thephenylalkene derivative of the general formula (II) in some cases.Examples of the catalyst are nickel catalysts such as divalent nickelcomplexes, for example, bis(triphenylphosphine) nickel chloride,bis(1,3-diphenylphosphinopropane) nickel chloride, nickelacetylactonate, etc. The catalyst is usually used in an amount of 0.001to 10 mole %, preferably 0.1 to 3 mole %, based on the benzyl halidederivative.

The reaction temperature is usually in a range of 0 to 80° C.,preferably 10 to 70° C.

Although the manner for the addition of the reactants is notparticularly restricted, the benzyl halide derivative is usually addeddropwise to the Grignard reagent solution during an appropriate periodof time.

The isolation of the phenylalkene derivative produced from the reactionmixture can be usually carried out in the following manner: After thecompletion of the reaction, the reaction mixture is posttreated withwater, an aqueous acidic solution, or an aqueous ammonium chloridesolution which are conventionally used for the decomposition of Grignardreagents to decompose the Grignard reagent, followed by the extractionof the phenylalkene derivative with an organic solvent. Then the desiredphenylalkene derivative can be isolated by conventional isolatingtechniques, for example, washing, concentration and distillation.

Examples of the phenylalkene derivative are 3-phenyl-1-propene,4-phenyl-1-butene, 5-phenyl-1-pentene, 6-phenyl-1-hexene,7-phenyl-1-heptene, 8-phenyl-1-octene, 9-phenyl-1-nonene,10-phenyl-1-decene, 3-(fluorophenyl)-1-propene,3-(chlorophenyl)-1-propene, 3-(bromophenyl)-1-propene,3-(iodophenyl)-1-propene, 4-(fluorophenyl)-1-butene,4-(chlorophenyl)-1-butene, 4-(bromophenyl)-1-butene,4-(iodophenyl)-1-butene, 5-(fluorophenyl)-1-pentene,5-(chlorophenyl)-1-pentene, 5-(bromophenyl)-1-pentene,5-(iodophenyl)-1-pentene, 6-(fluorophenyl)-1-hexene,6-(chlorophenyl)-1-hexene, 6-(bromophenyl)-1-hexene,6-(iodophenyl)-1-hexene, 7-(fluorophenyl)-1-heptene,7-(chlorophenyl)-1-heptene, 7-(bromophenyl)-1-heptene,7-(iodophenyl)-1-heptene, 8-(fluorophenyl)-1-octene,8-(chlorophenyl)-1-octene, 8-(bromophenyl)-1-octene,8-(iodophenyl)-1-octene, 9-(fluorophenyl)-1-nonene,9-(chlorophenyl)-1-nonene, 9-(bromophenyl)-1-nonene,9-(iodophenyl)-1-nonene, 10-(fluorophenyl)-1-decene,10-(chlorophenyl)-1-decene, 10-(bromophenyl)-1-decene, and10-(iodophenyl)-1-decene, wherein the substituents in the phenyl groupmay be positioned at any of R¹, R² and R³ ; and3-(methylphenyl)-1-propene, 3-(ethylphenyl)-1-propene,3-(propylphenyl)-1-propene, 3-(butylphenyl)-1-propene,4-(methylphenyl)-1-butene, 4-(ethylphenyl)-1-butene,4-(propylphenyl)-1-butene, 4-(butylphenyl)-1-butene,5-(methylphenyl)-1-pentene, 5-(ethylphenyl)-1-pentene,5-(propylphenyl)-1-pentene, 5-(butylphenyl)-1-pentene,6-(methylphenyl)-1-hexene, 6-(ethylphenyl)-1-hexene,6-(propylphenyl)-1-hexene, 6-(butylphenyl)-1-hexene,7-(methylphenyl)-1-heptene, 7-(ethylphenyl)-1-heptene,7-(propylphenyl)-1-heptene, 7-(butylphenyl)-1-heptene,8-(methylphenyl)-1-octene, 8-(ethylphenyl)-1-octene,8-(propylphenyl)-1-octene, 8-(butylphenyl)-1-octene,9-(methylphenyl)-1-nonene, 9-(ethylphenyl)-1-nonene,9-(propylphenyl)-1-nonene, 9-(butylphenyl)-1-nonene,0-(methylphenyl)-1-decene, 10-(ethylphenyl)-1-decene,10-(propylphenyl)-1-decene, 10-(butylphenyl)-1-decene,3-(methoxyphenyl)-1-propene, 3-(ethoxyphenyl)-1-propene,3-(propoxyphenyl)-1-propene, 3-(butoxyphenyl)-1-propene,4-(methoxyphenyl)-1-butene, 4-(ethoxyphenyl)-1-butene,4-(propoxyphenyl)-1-butene, 4-(butoxyphenyl)-1-butene,5-(methoxyphenyl)-1-pentene, 5-(ethoxyphenyl)-1-pentene,5-(propoxyphenyl)-1-pentene, 5-(butoxyphenyl)-1-pentene,6-(methoxyphenyl)-1hexene, 6-(ethoxyphenyl)-1-hexene,6-(propoxyphenyl)-1-hexene, 6-(butoxyphenyl)-1-hexene,7-(methoxyphenyl)-1-heptene, 7-(ethylphenyl)-1-heptene,7-(propoxyphenyl)-1-heptene, 7-(butoxyphenyl)-1-heptene,8-(methoxyphenyl)-1-octene, 8-(ethoxyphenyl)-1-octene,8-(propoxyphenyl)-1-octene, 8-(butoxyphenyl)-1-octene,9-(methoxyphenyl)-1-nonene, 9-(ethoxyphenyl)-1-nonene,9-(propoxyphenyl)-l-nonene, 9-(butoxyphenyl)-1-nonene,10-(methoxyphenyl)-1-decene, 10-(ethoxyphenyl)-1-decene,10-(propoxyphenyl)-1-decene, 10-(butoxyphenyl)-1-decene,3-(3,4-methylenedioxy-phenyl)-1-propene,3-(3,4-ethylenedioxy-phenyl)-1-propene,4-(3,4-methylenedioxy-phenyl)-1-butene,4-(3,4-ethylenedioxy-phenyl)-1-butene,5-(3,4-methylenedioxy-phenyl)-1-pentene,5-(3,4-ethylenedioxy-phenyl)-1-pentene,6-(3,4-methylenedioxy-phenyl)-1-hexene,6-(3,4-ethylenedioxy-phenyl)-1-hexene,7-(3,4-methylenedioxy-phenyl)-1-heptene,7-(3,4-ethylenedioxy-phenyl)-1-heptene, 8-(3,4-methylenedioxy-phenyl)-1-octene, 8-(3,4-ethylenedioxy-phenyl)-1-octene,9-(3,4-methylenedioxy-phenyl)-1-nonene,9-(3,4-ethylenedioxy-phenyl)-1-nonene,10-(3,4-methylenedioxy-phenyl)-1-decene,10-(3,4-ethylenedioxy-phenyl)-1-decene, etc.

Then the 1-bromoalkylbenzene derivative of the general formula (I) isprepared by reacting the phenylalkene derivative of the general formula(II) with hydrogen bromide.

Hydrogen bromide is usually used in the form of gas, but can be used inthe form of a hydrogen bromide solution in acetic acid or propionic acidwhich is readily commercially available. Hydrogen bromide may be used inan amount of at least the same mole as that of the phenylalkenederivative, usually in an amount of 1 to 10 moles per mole of it.

The reaction is usually carried out in the presence of a non-polarsolvent which is inert to the reaction. Examples of the solvent arealiphatic hydrocarbons such as pentane, hexane, cyclohexane, etc;aromatic hydrocarbons such as benzene, toluene, etc.; or the mixturethereof. The amount of the solvent to be used is not particularlyrestricted.

The reaction can be carried out in the presence of a radical initiator.Examples of the radical initiator are peroxides such as benzoylperoxide, tert.-butyl hydroperoxide, etc., AIBN, light, oxygen, etc. Theamount of the radical initiator to be used is not particularly limited.

The reaction temperature may be usually in the range of -50 to 50° C.,preferably at near a room temperature.

The reaction time depends on the reaction temperature, but is usually 5minutes to one hour. Even when reaction time is too long, adverseeffects would not be observed.

After the completion of the reaction, the desired 1-bromoalkylbenzenederivative can be isolated from the reaction mixture by conventionalisolating techniques, for example, extraction, phase separation anddistillation. If desired, it may be further purified by distillation andcolumn chromatography.

Examples of the 1-bromoalkylbenzene derivative of the general formula(I) are 3-phenyl-1-bromopropane, 4-phenyl-1-bromobutane,5-phenyl-1-bromopentane, 6-phenyl-1-bropmohexane,7-phenyl-1-bromoheptane, 8-phenyl-1-bromooctane, 9-phenyl-1-bromononane,10-phenyl-1-bromodecane, 3-(fluorophenyl)-1-bromononane,3-(chlorophenyl)-1-bromopropane, 3-(bromophenyl)-1-bromopropane,3-(iodophenyl)-1-bromopropane, 4-(fluorophenyl)-1-bromobutane,4-(chlorophenyl)-1-bromobutane, 4-(bromophenyl)-1-bromobutane,4-(iodophenyl)-1-bromobutane, 5-(fluorophenyl)-1-bromopentane,5-(chlorophenyl)-1-bromopentane, 5-(bromophenyl)-1-bromopentane,5-(iodophenyl)-1-bromopentane, 6-(fluorophenyl)-1-bromohexane,6-(chlorophenyl)-1-bromohexane, 6-(bromophenyl)-1-bromohexane,6-(iodophenyl)-1-bromohexane, 7-(fluorophenyl)-1-bromoheptane,7-(chlorophenyl)-1-bromoheptane, 7-(bromophenyl)-1-bromoheptane,7-(iodophenyl)-1-bromoheptane, 8-(fluorophenyl)-1-bromooctane,8-(chlorophenyl)-1-bromooctane, 8-(bromophenyl)-1-bromooctane,8-(iodophenyl)-1-bromooctane, 9-(fluorophenyl)-1-bromononane,9-(chlorophenyl)-1-bromononane, 9-(bromophenyl)-1-bromononane,9-(iodophenyl)-1-bromononane, 10-(fluorophenyl)-1-bromodecane,10-(chlorophenyl)-1-bromodecane, 10-(bromophenyl)-1-bromodecane,10-(iodophenyl)-1-bromodecane, 3-(methylphenyl)-1-bromopropane,3-(ethylphenyl)-1-bromopropane, 3-(propylphenyl)-1-bromopropane,3-(butylphenyl)-1-bromopropane, 4-(methylphenyl)-1-bromobutane,4-(ethylphenyl)-1-bromobutane, 4-(propylphenyl)-1-bromobutane,4-(butylphenyl)-1-bromobutane, 5-(methylphenyl)-1-bromopentane,5-(ethylphenyl)-1-bromopentane, 5-(propylphenyl)-1-bromopentane,5-(butylphenyl)-1-bromopentane, 6-(methylphenyl)-1-bromohexane,6-(ethylphenyl)-1-bromohexane, 6-(propylphenyl)-1-bromohexane,6-(butylphenyl)-1-bromohexane, 7-(methylphenyl)-1-bromoheptane,7-(ethylphenyl)-1-bromoheptane, 7-(propylphenyl)-1-bromoheptane,7-(butylphenyl)-1-bromoheptane, 8-(methylphenyl)-1-bromooctane,8-(ethylphenyl)-1-bromooctane, 8-(propylphenyl)-1-bromooctane,8-(butylphenyl)-1-bromooctane, 9-(methylphenyl)-1-bromononane,9-(ethylphenyl)-1-bromononane, 9-(propylphenyl)-1-bromononane,9-(butylphenyl)-1-bromononane, 10-(methylphenyl)-1-bromodecane,10-(ethylphenyl)-1-bromodecane, 10-(propylphenyl)-1-bromodecane,10-(butylphenyl)-1-bromodecane, 3-(methoxyphenyl)-1-bromopropane,3-(ethoxyphenyl)-1-bromopropane, 3-(propoxyphenyl)-1-bromopropane,3-(butoxyphenyl)-1-bromopropane, 4-(methoxyphenyl)-1-bromobutane,4-(ethoxyphenyl)-1-bromobutane, 4-(propoxyphenyl)-1-bromobutane,4-(butoxyphenyl)-1-bromobutane, 5-(methoxyphenyl)-1-bromopentane,5-(ethoxyphenyl)-1-bromopentane, 5-(propoxyphenyl)-1-bromopentane,5-(butoxyphenyl)-1-bromopentane, 6-(methoxyphenyl)-1-bromohexane,6-(ethoxyphenyl)-1-bromohexane, 6-(propoxyphenyl)-1-bromohexane,6-(butoxyphenyl)-1-bromohexane, 7-(methoxyphenyl)-1-bromoheptane,7-(ethoxyphenyl)-1-bromoheptane,7-(propoxyphenyl)-1-bromoheptane,7-(butoxyphenyl)-1-bromoheptane, 8-(methoxyphenyl)-1-bromooctane,8-(ethoxyphenyl)-1-bromooctane, 8-(propoxyphenyl)-1-bromooctane,8-(butoxyphenyl)-1-bromooctane, 9-(methoxyphenyl)-1-bromononane,9-(ethoxyphenyl)-1-bromononane, 9-(propoxyphenyl)-1-bromononane,9-(butoxyphenyl)-1-bromononane, 10-(methoxyphenyl)-1-bromodecane,10-(ethoxyphenyl)-1-bromodecane, 10-(propoxyphenyl)-1-bromodecane, and10-(butoxyphenyl)-1-bromodecane, wherein the substituents in the phenylgroup may be positioned at any of R¹, R² and R³ ; and3-(3,4-methylenedioxy-phenyl)-1-bromopropane, 3-(3,4-ethylenedioxy-phenyl)-1-bromopropane, 4-(3,4-methylenedioxy-phenyl)-1-bromobutane,4-(3,4-ethylenedioxy-phenyl)-1-bromobutane,5-(3,4-methylenedioxy-phenyl)-1-bromopentane,5-(3,4-ethylenedioxy-phenyl)-1-bromopentane,6-(3,4-methylenedioxy-phenyl)-1-bromohexane,6-(3,4-ethylenedioxy-phenyl)-1-bromohexane,7-(3,4-methylenedioxy-phenyl)-1-bromoheptane,7-(3,4-ethylenedioxy-phenyl)-1-bromoheptane,8-(3,4-methylenedioxy-phenyl)-1-bromooctane,8-(3,4-ethylenedioxy-phenyl)-1-bromooctane,9-(3,4-methylenedioxy-phenyl)-1-bromononane,9-(3,4-ethylenedioxy-phenyl)-1-bromononane,10-(3,4-methylenedioxy-phenyl)-1-bromodecane,10-(3,4-ethylenedioxy-phenyl)-1-bromodecane, etc.

The present invention also relates to a process for preparing an allylGrignard reagent of the general formula: ##STR10## wherein R⁴, R⁵ and R⁶independently represent a hydrogen atom or an alkyl group containing 1to 4 carbon atoms and X is the same as defined above, which can be usedas a starting substance for preparing the above phenylalkene derivative,comprising the step of reacting continuously an allyl halide derivativeof the general formula: ##STR11## wherein R⁴, R⁵ and R⁶ and X are thesame as defined above, with metal magnesium in an organic solvent toform the allyl Grignard reagent of the general formula (VI). The processis characterized in that the allyl halide derivative of the generalformula (VII) and metal magnesium are continuously added to the reactionsystem and the allyl Grignard reagent of the general formula (V) iscontinuously removed from the reaction system. The allyl Grignardreagent is very suitable for use as the Grignard reagent of the generalformula (V) used in the above process.

The substituents R⁴, R⁵ and R⁶ in the compounds of the general formulas(VI) and (VII) include a hydrogen atom, a methyl group, a ethyl group, an-propyl group, an isopropyl group, a n-butyl group, an isobutyl group,a tert.-butyl group, etc.

The reaction may be, for example, carried out as follows: Into areaction vessel having a branch, metal magnesium in an amount of 0 to 6times the allyl halide derivative in mole to be added during an initial1 hour, iodine in a small amount and a solvent are charged. The amountof the solvent to be charged is determined in such a manner that thereaction mixture begin to flow out of the reaction vessel through thebranch, for example, 1 hour after the start of the addition of the allylhalide derivative. Then the allyl halide derivative dissolved in thesolvent was continuously added through a pump. After heat is violentlygenerated to confirm the initiation of the reaction, the reactionmixture is cooled to a preset temperature. At the same time with theinitiation of the addition of the allyl halide derivative, metalmagnesium is also begun to be continuously added through a rotary solidintroducing apparatus in an equimolar amount to or more than that of theallyl halide derivative to be added. However, a large excessive amountof metal magnesium are not preferred since it is accumulated in thereaction system. The Grignard reagent which is formed and contained inthe reaction mixture flowing out the reaction vessel through the branchis quantitatively determined every unit time. The time when the contentof the Grignard reagent reaches a constant value is regarded as the timewhen the reaction system reaches a stationary state.

The above is the case wherein the residence time of the allyl halidederivative is 1 hour. The residence time can be controlled freely byvarying the amount of the allyl halide derivative added through thepump.

Examples of the solvent used are tetrahydrofuran, or the mixed solventthereof with tert.-butyl methyl ether or aromatic hydrocarbons such asbenzene, toluene, xylene, etc. From the point of the view of solventrecovery, the mixed solvent of tetrahydrofuran with tert.-butyl methylether or an aromatic hydrocarbon is more preferred than a single solventof tetrahydrofuran. When the mixed solvent is used, the mixing ratio isdetermined depending on the kind of the solvent used. For example, inthe case of the tetrahydrofuran--tert.-butyl methyl ether mixed solvent,a volume ratio of tert.-butyl methyl ether to tetrahydrofuran is from0.05 to 3.0, preferably from 0.5 to 1.5. In the case of thetetrahydrofuran/toluene mixed solvent, a volume ratio of toluene totetrahydrofuran is from 0.05 to 9, preferably from 0.4 to 5.5.

The amount of the solvent used for dissolving the allyl halidederivative which is continuously added is such that the concentration ofthe allyl halide derivative is in the range of 0.02 to 0.5, preferably0.05 to 0.2 mol/L. On the other hand, the amount of the solventinitially charged in the reaction vessel is not particularly restricteddepending on the volume of the reaction vessel. However, it is preferredto use the solvent in an amount of approximately half the volume atwhich the reaction mixture begin to flow out of the reaction vesselthrough the branch. When the amount is too small, the Wurtz typereaction tends to occur to decrease the yield of the Grignard reagent.On the other hand, the use of the solvent in a too large amount isuneconomical although it does not affect the yield.

The amount of the metal magnesium initially charged in the reactionvessel is in the range of 0 to 6 moles, preferably 1 to 3 moles per moleof the allyl halide derivative. Metal magnesium has not always to beinitially charged in the reaction vessel. On the other hand, the amountof the metal magnesium continuously added to the reaction vessel isusually in the range of not less than 1 mole, preferably 1 to 1.2 molesper mole of the allyl halide derivative. When it is less than 1 mole,the metal magnesium initially charged is consumed to lack magnesium inthe reaction system and hence the Wurtz type reaction tends to occur tolower the yield of the Grignard reagent. When it exceeds 1.2 moles, anunconsumed amount of magnesium is accumulated in the reaction systemalthough the yield is not affected. Magnesium can be added continuouslyor portionwise.

The amount of the allyl halide derivative added per unit time is notparticularly restricted provided it is in a range which can control thereaction temperature and the residence time of the allyl halide. Theamount which is suitable for a predetermined residence time should beselected.

The reaction is usually carried out at a temperature of -50 to 80° C.,preferably -10 to 60° C. The reaction time, which is the residence timeto the flowing out of the reaction mixture through the branch of thereaction vessel, is usually in the range of 0.1 to 5 hours, preferably0.5 to 3 hours.

The quantitative determination of the Grignard reagent in the reactionmixture flowed out would indicate that the content of the Grignardreagent therein become constant and the reaction system reaches astationary state in 5 to 15 hours usually.

The allyl Grignard reagent thus obtained is useful for the preparationof the phenylalkene derivative of the. general formula (II) and hencethe 1-bromoalkylbenzene derivative of the general formula (I). It canalso be used to be reacted with organic halides, ketones, aldehydes,esters, etc. to prepare intermediates for medicines, agrochemicals, etc.

According to the present invention, 1-bromoalkylbenzene derivatives,phenylalkene derivatives and allyl Grignard reagents can be obtained inhigh yields, high selectivities and high purities from the startingsubstances which can be easily available.

EXAMPLES

The present invention will be illustrated by Examples, but is notlimited thereto.

Example 1

Into a 3 L four-necked flask equipped with a stirrer, a thermometer, acondenser and a dropping funnel, 37.45 g (1.54 mole) of metal magnesiumin a shaved form and 0.1 g of iodine were charged. After the flask wasfilled with nitrogen, 250 ml of tetrahydrofuran and 750 ml of toluenewere added.

The flask was sufficiently cooled on an ice bath, and then 118 g (1.54mole) of allyl chloride was added dropwise at a temperature of 0 to 20°C. over a period of 2 hours with stirring.

The reaction mixture obtained was filtrated at a room temperature undera nitrogen atmosphere to remove unreacted magnesium. The filtrate wastransferred into another 3 L four-necked flask equipped with a stirrer,a thermometer, a condenser and a dropping funnel. Then 130 g (1.03 mole)of benzyl chloride was added dropwise at the same temperature over aperiod of 30 minutes, followed by stirring the mixture at the sametemperature for 4 hours.

After the completion of the reaction, the reaction mixture was added to300 ml of 5% sulfuric acid at a temperature of 0 to 10° C., followed bystirring for 30 minutes. Thereafter it was allowed to stand andphase-separated. The resulting oil layer was washed with 200 ml ofwater, followed by phase-separation. The resulting oil layer wastransferred to a 3 L four-necked flask equipped with a distillingcolumn. After distilling off the solvent at 110° C. under an atmosphericpressure, the residue was distilled under a reduced pressure of 80 mmHgat 91° C. to obtain 124.3 g of 4-phenyl-1-butene (yield 92%) which was acolorless liquid. An analysis by gas chromatography indicated the purityof 98.8%.

Example 2

Into a 3 L four-necked flask equipped with a stirrer, a thermometer, acondenser and a dropping funnel, 37.45 g (1.54 mole) of metal magnesiumin a shaved form and 0.1 g of iodine were charged. After the flask wasfilled with nitrogen, 500 ml of tetrahydrofuran and 500 ml oftert.-butyl methyl ether were added.

The flask was sufficiently cooled on an ice bath, and then 118 g (1.54mole) of allyl chloride was added dropwise at a temperature of 0 to 20°C. over a period of 2 hours with stirring.

The reaction mixture obtained was filtrated at a room temperature undera nitrogen atmosphere to remove unreacted magnesium. The filtrate wastransferred to another 3 L four-necked flask equipped with a stirrer, athermometer, a condenser and a dropping funnel. Then 130 g (1.03 mole)of benzyl chloride was added dropwise at the same temperature over aperiod of 30 minutes, followed by stirring the mixture at the sametemperature for 4 hours.

After the completion of the reaction, the reaction mixture was added to300 ml of 5% sulfuric acid at a temperature of 0 to 10° C., followed bystirring for 30 minutes. Thereafter it was allowed to stand andphase-separated. The resulting oil layer was washed with 200 ml ofwater, followed by phase-separation. The resulting oil layer wasdistilled in the similar manner to that in Example 1 to obtain 125.7 gof 4-phenyl-1-butene (yield 93%). An analysis of the product by gaschromatography indicated the purity of 98.0%.

Example 3

Example 1 was repeated except that 1.0 L of tetrahydrofuran was used asa solvent in place of the mixed solvent of 250 ml of tetrahydrofuran and750 ml of toluene, and 127.0 g (yield 94%) of 4-phenyl-1-butene wasobtained. The analysis of the product by gas chromatography indicatedthe purity of 98.0%.

Example 4

Into a 3 L four-necked flask equipped with a stirrer, a thermometer, acondenser and a dropping funnel, 37.45 g (1.54 mole) of metal magnesiumin a shaved form and 0.1 g of iodine were charged. After the flask wasfilled with nitrogen, 1.0 L of tetrahydrofuran were added.

The flask was sufficiently cooled on an ice bath, and then 118 g (1.54mole) of allyl chloride was added dropwise at a temperature of 0 to 20°C. over a period of 2 hours with stirring.

The reaction mixture obtained was filtrated at a room temperature undera nitrogen atmosphere to remove unreacted magnesium. The filtrate wastransferred to another 3 L four-necked flask equipped with a stirrer, athermometer, a condenser and a dropping funnel. 5.58 g (10.3 mmol) ofbis(1,3-diphenylphosphinopropane) nickel chloride was added thereto,followed by the dropwise addition of 130 g (1.03 mole) of benzylchloride at the same temperature over a period of 30 minutes. Then themixture was stirred at the same temperature for 4 hours.

A posttreatment was effected in the similar manner to that in Example 1to obtain 132.4 g (yield 96%) of 4-phenyl-1-butene. The analysis of theproduct by gas chromatography indicated the purity of 98.9%.

Example 5

To 85.5 g of toluene, 2.06 g (15.7 mmol) of 4-phenyl-1-butene preparedin Example 1 was added at a room temperature. The mixture was cooledwith ice, followed by stirring for 15 minutes. Then hydrogen bromide gaswas blown through the mixture under cooling with ice and the temperatureof the mixture was then elevated to a room temperature. After stirringfor 1 hour, the reaction mixture was washed with an aqueous sodiumbicarbonate solution, and then with water. Then the resulting oil layerwas concentrated with a rotary evaporator under a reduced pressure toobtain a colorless liquid. Hydrogen bromide gas was prepared in anamount of 10 mole equivalents (=157 mmol) according to the method knownin a literature (see "Inorganic Syntheses", Vol. I, p 149).

The liquid contained 4-phenyl-1-bromobutane and 4-phenyl-2-bromobutanein a ratio of 38:1 by mole.

Example 6

To 40 g of toluene, 4.01 g (30.6 mmol) of 4-phenyl-1-butene prepared inExample 1 was added at a room temperature. The mixture was cooled withice, followed by stirring for 15 minutes. Then 9.89 (30.6 mmol) of asolution containing 30% of hydrogen bromide in acetic acid was addeddropwise under cooling with ice and the temperature of the mixture wasthen elevated to the room temperature. After stirring the reactionmixture for 30 minutes, it was washed with an aqueous sodium bicarbonatesolution, and then with water. Then the resulting oil layer wasconcentrated by a rotary evaporator under a reduced pressure to obtain acolorless liquid.

The liquid contained 4-phenyl-1-bromobutane and 4-phenyl-2-bromobutanein a ratio of 20:1 by mole.

Example 7

To 85.5 g of toluene, 2.06 g (15.7 mmol) of 4-phenyl-1-butene preparedin Example 1 was added at a room temperature. The mixture was cooledwith ice, followed by stirring for 15 minutes. Then 0.1 g (0.41 mmol) ofbenzoyl peroxide was added and hydrogen bromide gas prepared in thesimilar manner to that in Example 1 was blown through the mixture undercooling with ice. The temperature of the mixture was then elevated to aroom temperature. After stirring the reaction mixture for 40 minutes, itwas washed with an aqueous sodium bicarbonate solution, and then withwater. Then the resulting oil layer was concentrated with a rotaryevaporator under a reduced pressure to obtain a colorless liquid.

The liquid contained 4-phenyl-1-bromobutane and 4-phenyl-2-bromobutanein a ratio of 41:1 by mole.

Comparative Example 1

3.13 g (115.9 mmol) of a solution containing 30% of hydrogen bromide inacetic acid was cooled with ice and 3.86 g (29.4 mmol) of4-phenyl-1-butene prepared in Example 1 was added dropwise thereto undercooling with ice. Thereafter the temperature of the mixture was elevatedto a room temperature. After stirring the reaction mixture for 15minutes, it was washed with an aqueous sodium bicarbonate solution, andthen with water. Then the resulting oil layer was concentrated with arotary evaporator under a reduced pressure to obtain a colorless liquid.

The liquid contained 4-phenyl-1-bromobutane and 4-phenyl-2-bromobutanein a ratio of 5:1 by mole.

Example 8

A 200 ml four-necked flask having a branch in such a manner that, whenthe content therein exceeded 120 ml, the excess amount flowed out of theflask through the branch was equipped with a stirrer, a thermometer, acondenser and a septum. 6.56 g (0.27 mol) of metal magnesium in a shavedform, 0.1 g of iodine and 60 ml of a mixed solvent containing 25% byvolume of tetrahydrofuran in toluene were charged therein.

The flask was cooled on an ice bath and 156.94 g (2.05 mole) of allylchloride dissolved in 1200 ml of a mixed solvent containing 25% byvolume of tetrahydrofuran in toluene was added dropwise therein at arate of 60 ml per hour through a pump while maintaining the temperatureof the reaction mixture at 25±2° C. After several minutes, heat wasgenerated with foaming, resulting in a rapid increase of the temperaturein the reaction system. Therefore it was cooled with an ice bath tomaintain it at 25±2° C. At the same time with the start of the dropwiseaddition of allyl chloride, metal magnesium was added at a rate of 2.19g (0.09 mole) per hour through a continuous rotary solid-introducingapparatus.

The reaction mixture which was flowed out through the branch was sampledevery 1 hour, followed by the reaction with n-hexanal. The analysis ofthe product by gas chromatography indicated that allyl magnesium bromidewas obtained in a yield of 82%.

Example 9

Example 8 was repeated except that a mixed solvent containing 50% byvolume of tetrahydrofuran in tert.-butyl methyl ether was used in placeof the mixed solvent containing 25% by volume of tetrahydrofuran intoluene. Allyl magnesium chloride was obtained in a yield of 80%.

Example 10

Example 8 was repeated except that tetrahydrofuran was used as a solventin place of the mixed solvent containing 25% by volume oftetrahydrofuran in toluene. Allyl magnesium chloride was obtained in ayield of 82%.

Example 11

Example 8 was repeated except that allyl bromide was used in place ofallyl chloride. Allyl magnesium bromide was obtained in a yield of 82%.

Example 12

Example 8 was repeated except that the reaction was carried out at 0° C.in place of 25° C. Allyl magnesium chloride was obtained in a yield of80%.

Example 13

Example 8 was repeated except that the reaction was carried out at 50°C. in place of 25° C. Allyl magnesium chloride was obtained in a yieldof 78%.

Example 14

Example 8 was repeated except that of metal magnesium was initiallycharged in an amount of 9.84 g (0.41 mole). Allyl magnesium chloride wasobtained in a yield of 78%.

Example 15

Example 8 was repeated except that a 300 ml four-necked flask having abranch in such a manner that, when the content therein exceeded 150 ml,the excess amount flowed out of the flask through the branch, was usedin place of the 200 ml four-necked flask. Allyl magnesium chloride wasobtained in a yield of 83%.

Example 16

Example 8 was repeated except that 4-chloro-2-methyl-2-butene was usedin place of allyl chloride. 3-methyl-2-butenyl magnesium chloride wasobtained in a yield of 83%.

Example 17

Example 8 was repeated except that 4-chloro-2-butene was used in placeof allyl chloride. 2-butenyl magnesium chloride was obtained in a yieldof 80%.

Example 18

Example 8 was repeated to form allyl magnesium chloride. The allylmagnesium chloride which flowed out of the flask through the branch wasaccumulated in a 3 L four-necked flask equipped with a stirrer, athermometer, a condenser and a dropping funnel which was placed under anitrogen atmosphere till the completion of the flowing-out of allylmagnesium chloride. Then 156 g (1.23 mole) of benzyl chloride was addeddropwise thereto at a temperature of 0 to 20° C. over a period of 45minutes, followed by stirring at the same temperature for 4 hours.

After the completion of the reaction, a posttreatment was effected inthe similar manner to that in Example 1 to obtain 147.7 g (yield 91%,based on benzyl chloride) of 4-phenyl-1-butene which was a colorlessliquid. An analysis of the product by gas chromatography indicated thepurity of 98.3%.

Example 19

300 g of toluene was added at a room temperature to 15.1 g (0.114 mole)of 4-phenyl-1-butene obtained in Example 18. The mixture wassufficiently cooled by an ice bath and hydrogen bromide prepared in thesimilar manner to that in Example 5 was blown through it under icecooling. Then the temperature of the mixture was elevated to a roomtemperature, followed by stirring for 1 hour. After the mixture waswashed with an aqueous sodium bicarbonate solution and then with water,the resulting oil layer was concentrated with a rotary evaporator toobtain a colorless liquid.

The liquid contained 4-phenyl-1-bromobutane and 4-phenyl-2-bromobutanein a ratio of 38:1 by mole.

Example 20

Example 8 was repeated to form allyl magnesium chloride. The allylmagnesium chloride which flowed out of the flask through the branch wasaccumulated in a 3 L four-necked flask equipped with a stirrer, athermometer, a condenser and a dropping funnel placed under a nitrogenatmosphere. A mixed solvent of toluene and tetrahydrofuran dissolvingallyl chloride was started to be added dropweise thereto. 2 hours afterthe start of the addition of the mixed solvent, 300 ml of a mixedsolvent of toluene and tetrahydrofuran (a content of terahydrofuran 25%by weight) dissolving 156 g (1.23 mole) of benzyl chloride was addeddropwise in the 3 L four-necked flask at a rate of 15 ml per hour at atemperature of 0 to 20° C. After the completion of the dropwiseaddition, the reaction mixture was stirred for 1 hour at the sametemperature. After the completion of the reaction, an aftertreatment waseffected in a similar manner to that in Example 1 to obtain 146.9 g(yield 90%, based on benzyl chloride) of 4-phenyl-1-butene which was acolorless liquid. An analysis of the product by gas chromatographyindicated the purity of 98.7%.

Example 21

300 g of toluene was added at a room temperature to 15.1 g (0.114 mole)of 4-phenyl-1-butene obtained in Example 20. The mixture wassufficiently cooled by an ice bath and hydrogen bromide gas prepared inthe similar manner to that in Example 5 was blown through the mixtureunder ice cooling. Then the temperature of the mixture was elevated to aroom temperature, followed by stirring for 1 hour. After the mixture waswashed with an aqueous sodium bicarbonate solution and then with water,the resulting oil layer was concentrated with a rotary evaporator undera reduced pressure to obtain a colorless liquid.

The liquid contained 4-phenyl-1-bromobutane and 4-phenyl-2-bromobutanein a ratio of 40:1 by mole.

What is claimed is:
 1. A process for preparing a phenylalkene derivativeof the formula: ##STR12## wherein R¹, R², R³ independently represent ahydrogen atom, a halogen atom, a lower alkyl group containing 1 to 5carbon atoms or a lower alkoxy group containing 1 to 5 carbon atoms, orR¹ and R² together form a methylenedioxy group or an ethylenedioxy groupwhen R³ is a hydrogen atom, and n is an integer of 1 to 10, comprisingthe steps of:reacting an alkenyl halide of the formula:

    CH.sub.2 ═CH--(CH.sub.2).sub.n-1 --X                   (III)

wherein X represents a chlorine atom or a bromine atom, and n is thesame as defined above, with metal magnesium to form a Grignard reagentof the formula:

    CH.sub.2 ═CH--(CH.sub.2).sub.n-1 --MgX                 (IV)

wherein X and n are the same as defined above; and then reacting theGrignard reagent of the formula (IV) with a benzyl halide derivative ofthe formula: ##STR13## wherein R¹, R², R³ and X are the same as definedabove, to form the phenylalkene derivative of the formula (II), whereinthe reaction of said Grignard reagent of the formula (IV) with saidhalide derivative of the formula (V) is carried out in the presence of anickel catalyst.
 2. The process of claim 1, wherein the organic solventis tetrahydrofuran or a mixed solvent thereof with tert.-butyl methylether or an aromatic hydrocarbon.
 3. A process for preparing aphenylalkene derivative of the formula (II) ##STR14## comprising thesteps of: reacting continuously an allyl halide derivative of theformula (VII) ##STR15## wherein R⁴, R⁵ and R⁶ are all hydrogen atoms andX represents a chlorine atom or a bromine atom with metal magnesium inan organic solvent to form an allyl Grignard reagent of the formula (VI)##STR16## then reacting the allyl Grignard reagent formed with thebenzyl halide derivative of the formula (V) in the presence of a nickelcatalyst in an organic solvent to form the phenylalkene derivative ofthe formula (II) ##STR17## wherein R¹, R² and R³ independently representa hydrogen atom, a halogen atom, a lower alkyl group containing 1 to 5carbon atoms or a lower alkoxy group containing 1 to 5 carbon atoms, orR¹ and R² together form a methylenedioxy group or an ethylenedioxy groupwhen R³ is a hydrogen atom, and n is 2.